GLP-2 is a 33 amino acid peptide expressed in a tissue-specific manner from the pleiotropic proglucagon gene, and thus part of the glucagon super-family of peptide hormones. Alternative post-translational processing of proglucagon occurs in pancreas, intestine and brain. Enzymatic cleavages in proglucagon produce numerous multifunctional peptide hormones involved in nutrient metabolism. The major bioactive hormones derived from proglucagon are in the pancreatic α-cells, and GLP-1 and GLP-2 in the intestinal L-cells and brain. It was first discovered to possess potent intestinotropic properties by Drucker et al. (see Proc. Natl. Acad. Sci., 1996, 93, (115), 7911-7916). GLP-2, as a natural intestinal-derived peptide, has been demonstrated to have a significant reparative activity for the mucosal epithelium of the small and large intestine. It has also been demonstrated to increase the ability of the intestine to digest and absorb nutrients, suggesting a potential therapeutic role in the treatment of intestinal insufficiency. Indeed, several studies have now confirmed that GLP-2 administration reduces or prevents intestinal damage in rodent models of colitis, enteritis, total parenteral nutrition and massive resection. Very recently, phase 2 clinical trials of GLP-2 have also been reported, in which patients with short bowel syndrome were demonstrated to exhibit an enhanced ability to absorb enteral nutrients after 30 days of GLP-2 administration, with apparently no undesirable side effects.
The principal metabolic pathway for GLP-2 clearance is through enzymatic degradation. GLP-2 has been shown to be rapidly degraded through the removal of its two N-terminal amino acids by dipeptidylpeptidase-IV (DPP-IV), which represents a major limitation because it leads to the complete inactivation of the peptide. As a result, the half-life of GLP-2 is thus quite short, and current GLP-2 treatment necessitates infusion or frequent injections. Renal clearance has also been shown to be involved in the clearance of GLP-2. The major action of GLP-2 involves stimulation of cell growth, and the mechanism coupling GLP-2 receptor activation, directly or indirectly, to cell proliferation has not been examined.
It has been shown that peptide analogs of native GLP-2 possess enhanced trophic activity at the small intestine as GLP-2 receptor agonists (see for example U.S. Pat. No. 5,990,077).
Although very useful, a critical disadvantage of GLP-2 peptides and analogs, as stated above, is their very short half-lives in vivo, which is typically not more than 2 minutes.
Inflammatory Bowel Disease (IBD) is a group of chronic disorders that cause inflammation or ulceration in the small and large intestines. It may even be life threatening, and there is currently no known cure. IBD commonly refers to ulcerative colitis (UC), limited to the colon and Crohn's disease (CD) which can involve the entire gastrointestinal tract, resulting in a chronic cycle of remissions and flares. Many pharmaceutical products are known to treat IBD, for example to suppress inflammation, to prevent flare-ups, to control symptoms such as pain or diarrhea, or to replace or supplement essential nutrients that are poorly absorbed because of extensive disease or surgery. Current treatment options include a wide variety of pharmaceutical products like aminosalicylates, corticosteroids, immune modulators, and anti-TNF-α agent, and are designed to reduce inflammation and relieve symptoms in addition to replacing lost fluids and nutrients. Most of these products however have a limited use in IBD because of their undesirable side effects on the body in general.
Approximately one million patients are treated for IBD every year in the United States and Europe, most of them generally suffering from either Crohn's disease or ulcerative colitis. In fact, it is not uncommon for subjects suffering from IBD to undergo radical surgery involving the removal of major parts of the intestine. Direct annual healthcare costs of IBD are approximately $US 700 million, and the total economic impact of both direct and indirect costs approximate between $2 and $3 billion a year worldwide. Existing treatments, while often providing relief, have some shortcomings.
U.S. Pat. No. 5,789,379 teaches GLP-2 analogs among which one has been developed as a long-acting compound (ALX-600™) and is currently in clinical trials. However, even if DPP-IV degradation of GLP-2 appears to be somehow prevented, its half-life remains limited by renal clearance, and does not exceed 2 minutes, as stated above.
A chimeric antibody (Remicade™) has been developed to bind specifically to human tumor necrosis factor alpha (TNFα) for the short-term treatment of Crohn's. This antibody is indicated for the reduction of the symptoms of moderate to severe Crohn's disease in patients who have had an inadequate response to conventionnal therapy with corticosteroids, other immunosuppressants and/or antibiotics. Nevertheless, serious side effects are observed with such treatment. For example, it has been associated with hypersensitivity reaction, serious infections including sepsis, as well as fatal infections. Its administration could further predispose patients to infections through TNF-blocking.
With the prevalence of IBD increasing in recent years, it would therefore be highly desirable to develop GLP-2 peptide derivatives or analogs capable of substantially maintaining the same level of activity, low toxicity and therapeutic advantages as GLP-2, but with a much longer in vivo half-life, thus avoiding the necessity for continuous administration thereof in the treatment of various diseases such as inflammatory bowel disease, Crohn's disease and ulcerative colitis representing the two major inflammatory bowel diseases.